The inhibitory receptors PD1 and LAG3 synergize in the regulation of immune tolerance and prevention of autoimmunity. However, they also limit tumor clearance and sterilizing immunity to chronic viral infections. PD1/LAG3 mediate T cell intrinsic control, but also modulate the development, homeostasis and function of regulatory T cells (Tregs). Thus, inhibitory receptors are critical for maintaining immune control but also represent a major barrier to effective anti-tumor and anti-viral immunity. Our recent studies have highlighted the synergistic utilization of PD1 and LAG3, in a variety of disease settings including autoimmunity, tumors and chronic viral infections. Whereas mice lacking either PD1 or LAG3 alone exhibit minimal immunopathology, mice lacking both PD1 and LAG3 develop lethal systemic autoimmune disease. We have also shown that combinatorial blockade of PD1 and LAG3 can reinvigorate exhausted T cells in mice with chronic viral infections and induce complete remission in mice with pre-existing tumors. The primary goal and long-term objective of this PPG is to determine the relative contribution of, and synergistic interaction between, inhibitory receptors in critical immune populations. The scope of the program project will focus on the interplay between PD1 and LAG3 in regulating CD4+ T cells, CD8+ T cells and Tregs in the modulation of tolerance and autoimmunity (Project 1), tumor immunity (Project 2) and chronic viral infection (Project 3). Our central hypothesis is that PD1 and LAG3 pathways synergize through cellular and molecular crosstalk leading to both overlapping and unique mechanisms that collectively regulate CD4+ T cell, CD8+ T cell and Treg function in autoimmunity, cancer and chronic viral infections. Given that PD1/LAG3 are expressed by all T cell subsets, it is not clear what impact the loss of PD1/LAG3 has on a particular cell type in a particular disease setting. A major strength of this PPG is the available of unique tools that will facilitate the `surgical' deletion of PD1 and/or LAG3 from specific T cell subpopulations constitutively or in a temporally controlled manner. This PPG will be supported by four cores; Administrative (Core A), Mutant Mouse (Core B), Functional Genomics and Computational Biology (Core C), and Immunopathology Cores (Core D).